Until now, most of the attention in genomics has been on sequencing. But in functional genomics sequence information alone is not enough to lead to important new drug and diagnostic discoveries. It is critical to understand how genes work, how and when they are expressed and what roles they play in health and disease. By Klaus Kristensen and Torben F Ørntoft.
Functional genomics is the research area which most likely will provide the discovery of breakthrough medical products by revealing thousands of new biological targets for the development of drugs.
Because mice and humans share many of the same fundamental biological and behavioural processes, this animal is one of the most significant laboratory models for human disease.
The large knowledge of the genetic make-up of the mouse, and the ability to compare it to the DNA of humans, has opened many avenues for designing new pharmaceuticals.
Methodologies
Other advantages of mouse models are the methodologies of genetic engineering developed specifically for this species. The mouse is the only animal in which it possible to deliberately turn on or silence specific genes.
Genetically engineered mice include mice with transgenes and mice with targeted mutations (aknockouts').
Transgenics carry a segment of foreign DNA that has been incorporated into the genome via nonhomologous recombination.
Targeted mutated mice are created by gene disruptions, replacements, or duplications through the process of homologous recombination between the exogenous (targeting) DNA and endogenous (target) gene.
The scientific community clearly recognises the potential of genetically engineered mice as preclinical models of human cancers.
Tissue-specific cancers
Genetically defined mouse models are now available in which tissue-specific cancers arise through very similar genetic etiologies as the corresponding human cancers.
Thus these models provide opportunities for identifying and characterising molecular mechanisms of tumorigenesis and for developing targeted cancer therapeutics.
DNA microarrays
The process of differential gene expression generates extraordinarily complex networks of gene interactions.
To understand the molecular mechanisms of health and disease, an understanding of these networks are needed. Thus, as the emphasis in genomics shifts from identifying genes to characterising their biological functions, knowledge of gene expression patterns becomes crucial.
Until now we have been working with the top of the iceberg in terms of the few thousand known genes.
Expressed sequence tags
From now on, more than 50 000 expressed sequence tags (ESTs) are available for evaluation during disease processes, during drug treatment, physiological stimulation, transgenic manipulation, etc, opens a complete new research approach.
DNA microarray technology allows researchers to scan thousands of genes for activity in cell and tissue systems. The technology is highly reproducible, and sensitive down to less than one copy of mRNA per cell.
Bioinformatic tools
Applied to microdissected tissue an enormous amount of information is acquired. To handle this information bioinformatic tools are needed, that will mine the data and present them in an intelligible format. In-silico discovery of homologous protein families based on ESTs is an attractive approach that is already being explored.
The explosion of information generated by large-scale genomics-related technologies has resulted in the exponential increase in the number of genes and proteins available for pharmaceutical and diagnostic research development, leading to the dramatic increase in the number of anti-cancer drugs undergoing clinical development.
Enquiry No 25
Klaus Kristensen is with Pipeline Biotech, Silkeborg, Denmark, and Torben F Ørntoft with Molecular Consult, Aabyhoej, Denmark.
